Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, considered as one of the most serious and widespread public health problem of the 21st century.
Excessive body weight is associated with various physical and mental diseases and conditions, particularly cardiovascular diseases, diabetes mellitus type 2, obstructive sleep apnea, certain types of cancer, osteoarthritis and depression. As a result, obesity has been found to reduce life expectancy. Once considered a problem only of high-income countries, obesity rates are rising worldwide and affecting both the developed and developing world.
To date, there is an ongoing search for an effective and safe treatment for obesity, abnormal fat-distribution and all health threatening conditions associated therefrom.
Fat tissue or adipose tissue is the loose connective tissue composed of adipocytes. Adipose tissue is derived from lipoblasts. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. Adipose tissue includes all fat tissue in the body including abdominal fat, epicardial fat and subcutaneous fat.
Adipose tissue has been recognized to participate in endocrine processes, including the production of hormones such as leptin, estrogen, resistin, and cytokine TNFα. Moreover, adipose tissue can affect other organ systems of the body and may lead to disease.
Obesity in humans and most animals does not depend on body weight, but on the amount of adipose tissue.
There are two types of adipose tissue: white adipose tissue (WAT), which primarily stores fat, and brown adipose tissue (BAT), which functions in the process of fat burning for heat production (Farmer S R, Gene & Development 22, 1269-1275 (2008), Petrovic N, JBC 258, 7153-7164 (2010)). The feasibility of WAT to BAT conversion was demonstrated, for example, by application of PPARγ agonists (Ohno H. et al., Cell Metabolism 15: 395-404 (2012)). However, from the whole organism point of view, PPARγ activation has also other effects on other tissues with the end result of increase in body weight in PPARγ agonists treated patients.
One optional strategy for treating obesity and related conditions, diseases and disorders associated with abnormal WAT distribution is to induce the conversion of WAT to BAT. Previous treatment of obesity in such mechanism of action included the use of thiazolidazine compounds which increased the body's sensitivity to insulin. Such compounds showed many adverse effects, including liver toxicity, bone loss, and weight gain.